Allogeneic stem cell transplantation (alloSCT) is a potentially curative therapy for hematologic malignancies and inherited hematopoietic stem cell disorders. However, graft vs. host disease (GVHD) is a major cause of morbidity and mortality following alloSCT. Strategies to reduce GVHD are limited due to their adverse effects on graft vs. tumor (GVT), stem cell engraftment, and immune reconstitution. Thus, a better understanding of the immunologic basis of GVHD and GVT is needed. We recently discovered that memory phenotype CD4 T cells do not cause GVHD, but can transfer immunity to a model antigen. This finding has been confirmed and extended by others and ourselves to a variety of GVHD scenarios, indicating that the inability of memory phenotype T cells to cause GVHD is a general phenomenon. Therefore, the transfer of memory cells during alloSCT is attractive as an approach to minimize GVHD while maximizing engraftment, immune reconstitution and even GVT. However, much remains unknown about the mechanisms that underlie the inability of memory T cells to mediate GVHD. A better understanding of memory T cell biology and functions after transplant is a substantial basic interest, and also of course would help in optimizing new therapeutic approaches. In Aim 1, we plan to test three hypotheses to explain this phenomenon: 1. The inability of memory cells to traffic to LN and PP prevents initial activation of memory cells by alloantigens; 2. The restricted TCR repertoire of memory cells reduces the frequency of alloreactive T cells, making memory cells inefficient inducers of GVHD; 3. A relative inability of memory cells to proliferate indefinitely leads to clonal exhaustion and failure to induce clinical GVHD. Regardless of the mechanisms preventing memory cells from inducing GVHD, the initial finding raises two important practical questions: can memory cells protect the recipient from infectious pathogens and can transferred memory cells mediate GVT? In Aim 2 we will use appropriate model systems to address these two questions. At the conclusion of these studies we will have learned a substantial amount both about why memory cells can be transferred during alloSCT without causing GVHD as well as the potential clinical value of such transfers. These studies can clearly help set the stage for applying this approach in rationally designed clinical pilot studies.